Sex-Specific Protection Against Diet-Induced Non-Alcoholic Fatty Liver Disease in TRPV1 Null Mice

Connell, P. J.; Bratz, I. N.; Andrei, S. R.; Eusebio, L.; DelloStritto, D. J.; Fahmy, J. N.; Ferrell, J. M.; Pathak, P.; Chiang, J. Y. L.; Damron, D. S.

doi:10.1101/403881

bioRxiv · 10.1101/403881

Sex-Specific Protection Against Diet-Induced Non-Alcoholic Fatty Liver Disease in TRPV1 Null Mice

Connell, P. J.·Bratz, I. N.·Andrei, S. R.·Eusebio, L.·DelloStritto, D. J.·Fahmy, J. N.·Ferrell, J. M.·Pathak, P.·Chiang, J. Y. L.·Damron, D. S.

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Abstract

ObjectivesTRPV1 channels have been linked to the development and progression of diabetes at multiple levels, including control of appetite and weight, regulation of pancreatic function, thermogenesis, metabolism and energy homeostasis. Despite this, little information is known regarding its role in liver homeostasis and nonalcoholic fatty liver disease (NAFLD).\n\nMethods and ResultsTo better understand the role of TRPV1 in liver metabolism, we explored the effects of a high fat/sugar diet (Western, 24-week regimen) in male and female wild type (WT) and TRPV1-null (V1KO) mice. Our data reveal that loss of the TRPV1 gene makes mice susceptible to diet-induced obesity and induces NAFLD. V1KO mice displayed gross phenotypic and gross morphological changes including insulin resistance, glucose intolerance, increased body mass and central adiposity on a western diet compared to WT counterparts. Western fed V1KO mice exhibited gross changes in liver morphology and size compared to western fed WT mice, which were supported with histological H&E and Oil Red O staining. Accompanying the liver changes, Western fed V1KO mice exhibited altered lipid profiles as demonstrated by elevated hepatic triglyceride, cholesterol and free fatty acid levels compared to western fed WT mice. Interestingly, female V1KO mice fed a western diet displayed significant protection against diet-induced obesity and the progression of NAFLD compared to their male counterparts. Taken together, these data suggest that loss of TRPV1 promotes fat accumulation, NAFLD development and changes in liver lipid profiles in male mice, the extent to which is less severe in female V1KO mice.\n\nConclusionIn conclusion, TRPV1 may be a protective therapeutic target for the prevention of NAFLD development in diet-induced obesity.

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Connell, P. J., Bratz, I. N., Andrei, S. R., Eusebio, L., DelloStritto, D. J., Fahmy, J. N., Ferrell, J. M., Pathak, P., Chiang, J. Y. L., Damron, D. S.. 2018-08-30. Sex-Specific Protection Against Diet-Induced Non-Alcoholic Fatty Liver Disease in TRPV1 Null Mice. https://doi.org/10.1101/403881

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